Oral cancer is the most common cancer of the head and neck with a worldwide annual incidence of >300,000 and great disease- and treatment-related morbidity and poor survival, which has improved only marginally in decades. The search for new approaches to control this disease include prevention and early detection, within oral leukoplakia, the most common oral premalignant lesion (OPL). The Nordic cancer registries are the only national registries in the world that include oral dysplasia and oral cancer, allowing a comprehensive large scale prospective study the oral leukoplakia-cancer sequence. Using these registries we were able to study several key issues in this field and found that OPL resection does not reduce cancer risk, COX2 expression was tightly linked to aneuploidy and that regular NSAID use is associated with a striking 62% lower risk of head and neck cancer, strong support for a pharmacologic approach targeting COX2. We found that DNA aneuploidy was the most powerfull predictor of cancer risk in OPL patients, predicting a 3-year cancer risk of >70%. Aneuploid oral cancer is associated with a poor prognosis. These studies build on a recent body of molecular risk results from MDACC and other groups and mark the arrival of molecular markers of clonality and genetic instability as standard risk assessment tools for oral leukoplakia patients and for study of the mechanisms of multifocal disease. This proposal is the first phase-Ill (cancer incidence) risk-based targeted management of OPLs, including combination molecular targeted therapy with a COX2 inhibitor (celecoxib) and an EGFR/HER2 inhibitor (EKB-569) in a 2X2 placebo-controlled design. We hypothesize that EGFR/HER2 and COX2 signaling pathways interact in oral carcinogenesis to promote genetic instability and cancer development and that targeted inhibition of these pathways will prevent or delay oral cancer development. The rationale for targeting COX2 and EGFR in this trial is that in head and neck carcinogenesis both targets pathways are activated, and preclinical models indicate anti-tumor activity of the single agents and enhanced activity of the combination. Furthermore, EGFR can be activated directly by ligand binding and indirectly by GPCRs (PGE2 is a GPCR ligand); and downstream mediators of the EGFR/HER2 signaling pathway can induce COX2 transcription and PGE2 production; therefore targeting both pathways simultaneously may prove more efficacious.